title: Involvement of highly sulfated chondroitin sulfate in the metastasis of the Lewis lung carcinoma cells.
abstract: The altered expression of cell surface chondroitin sulfate (CS) and dermatan sulfate (DS) in cancer cells has been demonstrated to play a key role in malignant transformation and tumor metastasis. However, the functional highly sulfated structures in CS/DS chains and their involvement in the process have not been well documented. In the present study, a structural analysis of CS/DS from two mouse Lewis lung carcinoma (3LL)-derived cell lines with different metastatic potentials revealed a higher proportion of Delta(4,5)HexUA-GalNAc(4,6-O-disulfate) generated from E-units (GlcUA-GalNAc(4, 6-O-disulfate)) in highly metastatic LM66-H11 cells than in low metastatic P29 cells, although much less CS/DS is expressed by LM66-H11 than P29 cells. This key finding prompted us to study the role of CS-E-like structures in experimental lung metastasis. The metastasis of LM66-H11 cells to lungs was effectively inhibited by enzymatic removal of tumor cell surface CS or by preadministration of CS-E rich in E-units in a dose-dependent manner. In addition, immunocytochemical analysis showed that LM66-H11 rather than P29 cells expressed more strongly the CS-E epitope, which was specifically recognized by the phage display antibody GD3G7. More importantly, this antibody and a CS-E decasaccharide fraction, the minimal structure recognized by GD3G7, strongly inhibited the metastasis of LM66-H11 cells probably by modifying the proliferative and invading behavior of the metastatic tumor cells. These results suggest that the E-unit-containing epitopes are involved in the metastatic process and a potential target for the diagnosis and treatment of malignant tumors.
authors.affiliation: Graduate School of Life Science, Hokkaido University, Sapporo 001-0021, Japan.
authors.forename: Fuchuan
authors.initials: F
authors.lastname: Li
authors.forename: Gerdy B
authors.initials: GB
authors.lastname: Ten Dam
authors.forename: Sengottuvelan
authors.initials: S
authors.lastname: Murugan
authors.forename: Shuhei
authors.initials: S
authors.lastname: Yamada
authors.forename: Taishi
authors.initials: T
authors.lastname: Hashiguchi
authors.forename: Shuji
authors.initials: S
authors.lastname: Mizumoto
authors.forename: Kayoko
authors.initials: K
authors.lastname: Oguri
authors.forename: Minoru
authors.initials: M
authors.lastname: Okayama
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugahara
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000502:physiology*; D004187:Disaccharides / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006025:Glycosaminoglycans / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D014018:Tissue Distribution
chemical_list: D004187:Disaccharides; D006025:Glycosaminoglycans; D002809:Chondroitin Sulfates